Next Article in Journal
Primary, Bilateral and Diffuse Renal Non-Hodgkin’s Lymphoma in a Young Woman Suffering from Turner Syndrome
Next Article in Special Issue
Sweat Chloride Testing and Nasal Potential Difference (NPD) Are Primary Outcome Parameters in Treatment with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators
Previous Article in Journal
Calcium-Sensing Receptor Polymorphisms at rs1801725 Are Associated with Increased Risk of Secondary Malignancies
Previous Article in Special Issue
CFTR Modulators: Does One Dose Fit All?
Article

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants

1
Department of Physiology, McGill University, Montréal, QC H3G 1Y6, Canada
2
Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne 3010, Australia
3
Research Center, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC G1V 4G5, Canada
4
Adult Cystic Fibrosis Clinic, Montreal Chest Institute, McGill University, Montréal, QC H4A 3J1, Canada
5
Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
*
Authors to whom correspondence should be addressed.
Academic Editor: Cornelis K. van der Ent
J. Pers. Med. 2021, 11(7), 643; https://doi.org/10.3390/jpm11070643
Received: 16 June 2021 / Revised: 30 June 2021 / Accepted: 5 July 2021 / Published: 7 July 2021
(This article belongs to the Special Issue Cystic Fibrosis and Personalized Medicine)
Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients. View Full-Text
Keywords: cystic fibrosis; cystic fibrosis transmembrane conducatance regulator (CFTR); CFTR modulator combination; primary human nasal epithelia; CFTR missense mutations; precision medicine cystic fibrosis; cystic fibrosis transmembrane conducatance regulator (CFTR); CFTR modulator combination; primary human nasal epithelia; CFTR missense mutations; precision medicine
Show Figures

Figure 1

MDPI and ACS Style

Veit, G.; Velkov, T.; Xu, H.; Vadeboncoeur, N.; Bilodeau, L.; Matouk, E.; Lukacs, G.L. A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants. J. Pers. Med. 2021, 11, 643. https://doi.org/10.3390/jpm11070643

AMA Style

Veit G, Velkov T, Xu H, Vadeboncoeur N, Bilodeau L, Matouk E, Lukacs GL. A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants. Journal of Personalized Medicine. 2021; 11(7):643. https://doi.org/10.3390/jpm11070643

Chicago/Turabian Style

Veit, Guido, Tony Velkov, Haijin Xu, Nathalie Vadeboncoeur, Lara Bilodeau, Elias Matouk, and Gergely L. Lukacs 2021. "A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants" Journal of Personalized Medicine 11, no. 7: 643. https://doi.org/10.3390/jpm11070643

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop